Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from the 8-nitrogen of lysine residues on histone as well as non-histone proteins. Such posttranslational modifications can regulate numerous cellular processes, including gene expression, making these enzymes attractive targets for the treatment of cancer as well as neurological, metabolic, neoplastic, inflammatory, autoimmune, heteroimmune, and infectious diseases. These important enzymes can be divided into the NAD+-dependent Sirtuins (class III) and the Zn-dependent HDACs. The latter can be further divided into three classes, one of which is split into two subclasses class I (HDACs 1, 2, 3, and 8), class IIa (HDACs 4, 5, 7, and 9), class IIb (HDACs 6 and 10), and class IV (HDAC11). Currently, most of the clinically relevant HDAC inhibitors (i.e., vorinostat, romidepsin, and valproic acid) inhibit multiple HDAC isoforms and exhibit significant toxicity. However, it is believed that selective inhibition of only the desired HDAC isoforms can lead to drugs that are better tolerated and results in fewer side effects.
There is much to be understood about the family of HDACs, including the varying functions of different HDACs and the range of HDAC substrates. In order to learn more about the role that the individual HDACs play, it is important to develop compounds showing selectivity for individual isoforms or small subsets of these isoforms. While some degree of isoform selectivity has been shown by a few compounds, this problem of identifying selective inhibitors is far from solved, and is complicated by the interactions of the HDACs with each other as well as other proteins (cofactors) that can possibly alter their interaction with various inhibitors (Glaser, et al., Biochem. Biophys. Res. Commun., 325, 683-690 (2004)). Additionally, until now, medicinal chemists have focused on developing compounds selective for either a single isoform or a few isoforms within the same class. The possibility of achieving selectivity for HDAC isoforms belonging to different classes is also an important problem to be solved. Clinically, the optimal dose, timing and duration of therapy, as well as the most appropriate agents to combine with HDAC inhibitors, are also still to be defined.
There is a need to identify specific/selective HDAC inhibitors and to identify the structural features required for potent HDAC inhibitory activity.